The TRPM subfamily of transient receptor potential channels includes a number of members which are involved in cell proliferation or cell survival. TRPM2, the second member to be cloned, has a key role in the response to oxidative stress. After exposure to oxidant stress, TNFα, concanavalin A, or amyloid β-peptide, ADP-ribose is produced, which binds to a NUDT9-H domain in the C terminus and is a key regulator of channel opening and calcium influx. The important roles of TRPM2 isoforms in cell proliferation and oxidant-induced cell death have been well established in divergent cell types using a broad range of techniques including overexpression, channel knockout, depletion, or inhibition, and calcium chelation. Related to its central role in oxidative stress-induced cell injury, TRPM2 has been shown to mediate a number of disease processes. TRPM2 is involved in regulation of metabolism in diabetes (insulin secretion, β-cell injury, and insulin resistance), and obesity. It has a role in inflammation, immunity, and cancer. Modulation of TRPM2 may be able to ameliorate a number of these disease processes as well as those resulting from ischemia–reperfusion injury, vascular endothelial damage, and traumatic brain injury. A review of the involvement of TRPM2 in these physiological and pathophysiological processes, and its tremendous potential as a drug target is presented below.